Identifying ER-response genes in low-grade serous ovarian cancer for predictive biomarker discovery
Nelson Wong1,6, Hannah Kim1,2,6, Marta Llaurado Fernandez2,6, Yen-Yi Lin3, Robert Bell3, Anne Haegert3, Rebecca Wu1, Yuen Yee Leung2,6, Gurdial Dhillon2, Stanislav Volik3, Lilly McLellan2, Stephane Le Bihan3, Yuzhuo Wang1,3, Colin Collins3, Martin Koebel4, Cheng-Han Lee5, Mark S Carey2,6.
1Experimental Therapeutics, BC Cancer, Vancouver, BC, Canada; 2Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC, Canada; 3Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada; 4Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada; 5Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB, Canada; 6Clinical Research, BC Cancer, Vancouver, BC, Canada
Introduction
Low-grade serous ovarian carcinoma (LGSOC) is a rare cancer that occurs in younger women. Most are characterized by estrogen receptor (ER) and progesterone receptor (PR) expression. Treatment with anti-estrogen therapies (AET) is common; yet their effectiveness is unclear. Thus, there is a need to characterize ER-reponse genes in LGSOC to identify predictive biomarkers.
Methods
LGSOC samples were implanted under the renal capsules of female immunocompromised mice. The mice were ovariectomized. One group of mice were implanted with subcutaneous estradiol (E2) pellets, while the control group was E2-deprived. After two weeks, the tumor pieces were surgically recovered for snap freezing or fixation. The fixed tissues were processed for paraffin-embedding, and sections were stained for hematoxylin/eosin, ER, PR, and Ki-67. The snap frozen tissues were processed for RNA sequencing.
Results
We successfully implanted 7 treatment-naïve ER+ LGSOC tumours and 2 ER- LGSOC patient-derived xenografts (negative controls). Reduction of Ki-67 IHC staining (indicative of decreased proliferation) was observed in two ER+ cases after oophorectomy and PR expression was observed with E2 stimulation. We then compared mRNA expression profiles between the E2-supplemented and E2-deprived tumours and identified over 300 differentially expressed genes Only a small subset of these genes overlapped with the hallmark breast cancer ER-response genes.
Conclusions
Using a unique model system, we have identified functional candidate ER-response genes in LGSOC to discover predictive biomarkers of AET responsiveness. Our results suggest that LGSOC has a very different ER-response gene set compared to breast cancer, indicating substantial differences in cancer biology. Our next step is to create a Nanostring gene panel to evaluate the expressions of these genes in AET long-responders and short-responders, such that predictive biomarkers of AET can be identified for clinical use.
This work was funded by OvCAN/Ovarian Cancer Canada-Cancer Research Society Grant from Ovarian Cancer Canada and Cancer Research Society. The authors wish to thank the patients and their family for support.